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PubMed2006

Steroidogenic alterations and adrenal androgen excess in PCOS.

BACKGROUND: This cross-sectional study was undertaken to improve our understanding of the steroidogenic alterations leading to adrenal hyperandrogenism in polycystic ovarian syndrome (PCOS). METHODS: Two-hundred and thirty-four women with clinical and biochemical features suggestive of PCOS underwent metabolic and hormonal evaluation. We used the androstenedione/DHEAS ratio as a surrogate for the level of ovarian 3betaHSD activity. We then selected the 90th percentile for the ratio in those with elevated DHEAS (>9 micromol/l) as the cut-off level beyond which excess DHEAS production will be minimized by excess ovarian 3betaHSD activity. This cut-off level was at a ratio of 1.5 and all PCOS women were then divided into two groups, the higher (>1.5) being the group with excess ovarian 3betaHSD activity. We hypothesized that women with a high ratio would be unlikely to have DHEAS excess due to the rapid conversion of DHEA to androstenedione. Those with a low ratio (concordant ovarian and adrenal steroidogenesis) could then either have high DHEAS or normal DHEAS, depending on whether CYP17 activity was higher or lower respectively. RESULTS: Insulin resistance was found to be associated with decreased CYP17 activity while irregular cycles and neuroendocrine dysfunction were determined to be associated with higher ovarian 3betaHSD activity. CONCLUSION: Adrenal androgen excess in PCOS seems to be related to insulin sensitivity as well as decreased activity of 3betaHSD, the latter being preferentially present in those women with regular cycles or without neuroendocrine dysfunction.

Adolescent↗

PubMed2001

Metformin to restore normal menses in oligo-amenorrheic teenage girls with polycystic ovary syndrome (PCOS).

PURPOSE: To describe our clinical experience in using Metformin combined with a high protein-low carbohydrate diet to restore normal menstrual cycles in teenaged females with polycystic ovary syndrome (PCOS). METHODS: To enter the study, patients had to have well-documented PCOS, be oligo- (six cycles or less in the preceding year) or amenorrheic (absence of menstrual cycles for 1 year), and not have exclusionary diseases or drugs. Accompanying a high protein-low carbohydrate diet, Metformin (1.5-2.55 g/day) was given for 10.5 +/- 6.4 months (range, 4.5-26.5 months). Follow-up every 8-10 weeks for > or =6 months was scheduled with interval history, review of menstrual status, assessment of any Metformin-related side effects, brief physical examination, and determination of weight and blood pressure. RESULTS: All 11 girls had normal fasting blood glucose and glycohemoglobin. Pre-Metformin, five girls were amenorrheic, three had only one menstrual cycle in the previous year, and three had > or =6 cycles/year. With Metformin, 10 of 11 girls (91%) resumed regular normal menses; 39% of 38 follow-up visits with regular normal menstrual cycles were ovulatory with normal luteal-phase serum progesterone (> or =2.3 ng/mL). Of the 11 girls, nine (82%) lost weight; five girls lost > or =11 lb and seven lost > or =5 lb. After adjusting for weight reduction, with Metformin, estradiol and progesterone rose (p =.0014,.027, respectively) (changes consistent with resumption of regular normal menses), total plasma cholesterol fell (p =.026), and there was a downward trend in testosterone (p =.068). CONCLUSION: Metformin safely ameliorates the endocrinopathy of PCOS in previously oligo-amenorrheic teenage females with PCOS, facilitating resumption of normal menses in most girls.

Adolescent↗

PubMed2004

In-vitro maturation of immature oocytes for infertile women with PCOS.

Immature oocyte retrieval followed by in-vitro maturation (IVM) is a promising potential treatment option, especially for women who are infertile through polycystic ovarian syndrome (PCOS). Although the pregnancy and implantation rates of IVM treatment are not as high as conventional IVF treatment, IVM treatment has many advantages for infertile women with PCOS, because this group of patients is extremely sensitive to stimulation with exogenous gonadotrophins and is at increased risk of developing ovarian hyperstimulation syndrome (OHSS). Different protocols have been used before immature oocyte retrieval, indicating that there are beneficial effects with FSH or LH priming on oocyte maturation. To date, the clinical pregnancy and implantation rates obtained from IVM treatment in infertile women with PCOS are approximately 30-35% and 10-15% respectively. Therefore, as an option, IVM treatment can be offered to women with PCOS instead of conventional IVF treatment with ovarian stimulation.

Cell Culture Techniques↗

PubMed2004

Ultrasound evaluation of PCO, PCOS and OHSS.

Polycystic ovary syndrome (PCOS) and the concomitant androgen excess may be particularly distressing and disruptive for women. Thus, PCOS requires a prompt diagnosis and adequate treatment. However, the criteria used for diagnosis and definition of PCOS are as heterogeneous as the pathology itself. The advent of ultrasonographic examination of the ovaries has provided the biggest single contribution to the diagnosis of PCOS, having a high concordance rate with laparoscopy and histological examination. In fact, the assessment of ovarian morphology by transvaginal ultrasound and Doppler flow analysis of both intra-ovarian and uterine arteries seems to provide an insight into the pathological state and the degree of progression of the disease, and may be useful in the prevention and management of ovarian hyperstimulation syndrome during ovarian stimulation.

Arteries↗

PubMed1999

Endocrine and metabolic effects of octreotide, a somatostatin analogue, in lean PCOS patients with either hyperinsulinaemia or lean normoinsulinaemia.

The effects on insulin secretion and on the glycaemic and androgen status before and after short-term treatment with octreotide were evaluated in 16 normal weight patients with polycystic ovarian syndrome (PCOS). Hyperinsulinaemia was determined by measuring the insulin response after oral glucose tolerance test (OGTT). Seven patients (group A) were classified as normoinsulinaemic, while nine patients (group B) were considered hyperinsulinaemic according to insulin response after OGTT. Octreotide treatment did not modify either glycaemic or insulinaemic response after OGTT, or androgen profile, in normoinsulinaemic patients. On the contrary, a significant decrease in the basal concentrations of luteinizing hormone (LH), testosterone and androstenedione, and a significant increase in serum concentrations of sex hormone-binding globulin (SHBG) were observed in the hyperinsulinaemic group of patients, in which we observed also a significant decrease of insulinaemic response and a decompensation of the glycaemic profile after OGTT. Our study is the first report showing that: (i) octreotide does not appear to significantly influence pituitary release of gonadotrophins in this group of PCOS patients; (ii) octreotide is able to reduce insulin release, LH and androgen concentrations in lean PCOS patients with hyperinsulinaemia. Due to the presence of a decompensation of glucose homeostasis during treatment, octreotide does not seem advisable for long-term therapy of hyperandrogenism in lean PCOS patients with hyperinsulinaemia.

Adult↗

PubMed2001

Clinical, endocrine and metabolic effects of acarbose, an alpha-glucosidase inhibitor, in PCOS patients with increased insulin response and normal glucose tolerance.

BACKGROUND: The aim of this study was to evaluate whether treatment with acarbose, an alpha-glucosidase inhibitor, improved hyperandrogenic symptoms, insulin and androgen serum concentrations in hyperinsulinaemic patients with polycystic ovary syndrome (PCOS). METHODS: 30 hyperinsulinaemic women with PCOS and 15 controls were evaluated. Patients were randomized, using a computer-generated randomization list, into two groups of 15 each and treated with placebo or 300 mg/day of acarbose for three months. Hirsutism and acne/seborrhoea scores, hormonal and sex hormone binding globulin serum concentrations, glycaemia and insulin responses to a standard oral glucose load (75g) were measured in all patients before and after three months of treatment. RESULTS: A significant reduction of the acne/seborrhoea score was observed in patients treated with acarbose and eight of them resumed a regular menstrual rhythm. These clinical improvements were associated with a significant reduction of the insulin response to glucose load, a significant decrease of LH, total testosterone and androstenedione and with a significant increase of sex hormone binding globulin serum concentrations. The serum concentrations of FSH, dehydroepiandrosterone sulphate, prolactin and 17alpha-hydroxyprogesterone did not change significantly. No clinical, metabolic and hormonal modifications were observed in PCOS patients treated with placebo. CONCLUSIONS: This is the first report showing a reduction of the acne/seborrhoea score in hyperinsulinaemic patients with PCOS treated with acarbose. This improvement was associated with a significant decrease of the insulin response to oral glucose load and of LH and androgen serum concentrations and with a significant rise of sex hormone binding globulin concentration.

Acarbose↗

PubMed2002

Polycystic ovaries in childhood: a common finding in daughters of PCOS patients. A pilot study.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a controversial endocrine pathology and, recently, it has been suggested that the condition is hereditary. The aim of this study was to prospectively determine in daughters of patients with PCOS, by ultrasonographic (US) and colour Doppler analyses, the incidence of polycystic ovaries and search any correlation with specific hormonal parameters. METHODS: Fifteen prepubertal offspring (Group I) of patients with PCOS and 10 normal control prepubertal girls (Group II) were submitted to clinical, auxological, and basal hormonal assay. In addition all patients were submitted to US and colour Doppler ovarian and uterine evaluation. RESULTS: Among Group I girls the prevalence of polycystic ovaries was 93%, whereas no subjects among Group II had polycystic ovaries. The ovarian volume (2.76 +/- 1.21 ml versus 0.87 +/- 0.46 ml; P < 0.001) and the number of small sized follicles (5.36 +/- 2.2 versus 0.75 +/- 0.92; P < 0.001) were significantly higher in Group I than Group II patients. In addition, a normal stromal score and an absent stromal vascularization was observed in the control group. The hormone levels did not differ between the two groups. CONCLUSION: In conclusion we speculate that polycystic ovaries in childhood may be considered a sign of genetic predisposition to PCOS and that environmental factors may express the adult clinical and hormonal presentation of the syndrome.

Age of Onset↗

PubMed2002

Three-dimensional assessment of ultrasound features in women with clomiphene citrate-resistant polycystic ovarian syndrome (PCOS): ovarian stromal volume does not correlate with biochemical indices.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder affecting women of reproductive age. The syndrome is characterized by a combination of polycystic ovarian morphology, clinical features and biochemical indices. The objective of this prospective observational study was to investigate the relationship between the total ovarian volume and the ovarian stromal volume, measured using a three-dimensional (3D) ultrasound scan, with biochemical indices of PCOS. METHODS: Twenty-three infertile women (mean age +/- SD: 31 +/- 3.1 years; range: 26-37) with clomiphene citrate-resistant PCOS were examined. Early follicular phase (days 2-4) serum FSH, LH and testosterone concentrations were measured following a withdrawal bleed. Total ovarian volume, stromal volume, pre-antral follicle (<10 mm) number and total follicular volume were measured by 3D transvaginal ultrasound. RESULTS: Total ovarian volume, follicular volume and follicle number correlated positively with serum FSH and LH, but not testosterone, concentrations. Ovarian stromal volume correlated strongly with total ovarian volume only, but not with serum FSH, LH or testosterone concentrations. CONCLUSIONS: These findings demonstrate an association of the total ovarian volume, pre-antral follicle number and total follicular volume with some of the biochemical indices of PCOS, but no association was observed between ovarian stromal volume and these indices.

Adult↗

PubMed2004

Six-month treatment with low-dose dexamethasone further reduces androgen levels in PCOS women treated with diet and lifestyle advice, and metformin.

BACKGROUND: The purpose of this study was to investigate the effect of low-dose dexamethasone on androgen levels in women with polycystic ovary syndrome (PCOS) treated with diet and lifestyle counselling, and metformin. METHODS: A prospective, randomized, double blind, placebo-controlled study was carried out. Thirty-eight women with PCOS were randomized to either dexamethasone 0.25 mg daily or placebo for 26 weeks. All received diet and lifestyle counselling at inclusion and metformin 850 mg three times daily during the whole study. Main outcome measures were: androgen levels, body mass index (BMI), insulin c-peptide, fasting glucose and serum lipids. Two-tailed t-tests and Pearson's statistics were used. RESULTS: Compared with the placebo, dexamethasone reduced testosterone by 27%, androstenedione by 21%, dehydroepiandrosterone sulphate by 46% and free testosterone index by 50% in women with PCOS treated with diet and lifestyle advice, and metformin. BMI, fasting glucose, insulin c-peptide and serum lipid levels were unaffected. CONCLUSIONS: Six-month, low-dose dexamethasone treatment further reduces androgen levels in metformin-treated PCOS women.

Adult↗

PubMed2004

Is insulin resistance an essential component of PCOS?: The influence of confounding factors.

Insulin resistance is often considered a regular component of polycystic ovary syndrome (PCOS). Many interventional studies assume a state of insulin resistance in all patients. However, the evidence is based on small samples that are often insufficient to adjust for significant confounding factors. Moreover, several studies have not confirmed differences in insulin sensitivity between women with PCOS and healthy controls, especially in non-obese patients. This debate article provides an overview of the data published regarding the presence of abnormal or normal insulin sensitivity in PCOS. In conclusion, available data offer evidence that a substantial subgroup of women with PCOS have insulin sensitivity comparable with healthy controls if matched carefully for potential confounding factors.

Female↗

PubMed2004

Women with polycystic ovary syndrome (PCOS) often undergo protracted treatment with metformin and are disinclined to stop: indications for a change in licensing arrangements?

Women with polycystic ovary syndrome (PCOS) are increasingly being treated with metformin as an insulin sensitizing agent to reduce symptoms of hyperandrogenism and promote fertility. Indications such as hirsutism and cycle regulation require long term treatment. The drug is also being used through pregnancy. It is not licensed for any indication specific to PCOS, which means that much of this prescribing is taking place in an environment short of reliable information concerning safety. We describe the failure of recruitment to a study undertaken to explore the effects of metformin treatment discontinuation in women with PCOS, to provide both clinical and aetiological information. The study failed because the patients did not wish to stop treatment, and it illustrates the problems facing doctors working in this area. To achieve a safer prescribing environment, we recommend that action be taken by the manufacturer of metformin to work with regulatory agencies on a European base to extend prescribing indications for metformin to women with PCOS.

Clinical Trials as Topic↗

PubMed2006

The use of metformin for women with PCOS undergoing IVF treatment.

BACKGROUND: Metformin appears to improve reproductive function in some women with polycystic ovary syndrome (PCOS). We wished to explore the effect of metformin in women with PCOS undergoing IVF. METHODS: A randomized, placebo-controlled, double-blind study was carried out between 2001 and 2004. Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were randomized to receive metformin (MET), 850 mg, or placebo (PLA) tablets twice daily from the start of the down-regulation process until the day of oocyte collection. The primary outcome was to be an improvement in the overall fertilization rate. RESULTS: One-hundred and one IVF/ICSI cycles were randomized to receive metformin (52) or to receive placebo (49). There was no difference in the total dose of rFSH required per cycle (median dose: MET = 1200 U, PLA = 1300 U; P = 0.937). The median number of oocytes retrieved per cycle (MET = 17.2, PLA = 16.2; P = 0.459) and the overall fertilization rates (MET = 52.9%, PLA = 54.9%; P = 0.641) did not differ. However, both the clinical pregnancy rates beyond 12 weeks gestation per cycle (MET = 38.5%, PLA = 16.3%; P = 0.023) and per embryo transfer (MET = 44.4%, PLA = 19.1%; P = 0.022) were significantly higher in those treated with metformin. Furthermore, a significant decrease in the incidence of severe ovarian hyperstimulation syndrome (OHSS) was observed (MET = 3.8%, PLA = 20.4%; P = 0.023), and this was still significant after adjustment for BMI, total rFSH dose and age (OR = 0.15; 95% CI: 0.03, 0.76; P = 0.022). CONCLUSION: Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS.

Adult↗

PubMed2000

[Results of clomiphene citrate ovarian stimulation vs laparoscopic electrocoagulation of the ovaries in infertile women with PCOS].

OBJECTIVE: To assess the results of clomiphene citrate ovarian stimulation vs laparoscopic electrocoagulation of the ovaries in infertile women with PCOS. DESIGN: 47 women with PCOS were included into the study. 25 of them had ovarian stimulation using clomiphene citrate (100 mg for 5 consecutive days, during 6 cycle) and 22 underwent laparoscopic electrocoagulation of the ovary (6 cycle follow-up) No significant differences were detected between age and body mass index. RESULTS: In the first group ovulatory cycles were confirmed in 68% of women, pregnancy rate was 28%. In the second group ovulations were observed in 90.9% of women and pregnancy rate was 63.6%. There were statistically significant differences. CONCLUSION: In summarising, the results showed lower, statistically significant differences in pregnancy rate in the treatment of infertility associated with PCOS. It seems that the much more successful result of the PCOS therapy may be achieved after laparoscopic ovarian diathermy in comparison with stimulation of the ovaries with CC.

Clomiphene↗

PubMed2001

Divalent cations in women with PCOS: implications for cardiovascular disease.

Polycystic ovary syndrome (PCOS) patients are known to have a high incidence of insulin resistance and glucose intolerance and tend to be at eventual high risk of hypertension, diabetes mellitus and cardiovascular disease. It has been repeatedly shown that a low serum ionized magnesium (Mg2+) and a high ionized calcium to magnesium (Ca2+/Mg2+) ratio is often associated with insulin resistance, cardiovascular problems, diabetes mellitus and hypertension. We were therefore interested in assessing the serum divalent cation profile of PCOS patients compared with that of normal women of similar age. We found significantly lower serum Mg2+ and total magnesium and a significantly higher serum Ca2+/Mg2+ ratio in the PCOS patients compared with the controls. No correlation was found, however, between the serum concentrations of steroid hormones (estrogen, progesterone and testosterone), or any of the cations in the PCOS patients or the controls.

Adult↗

PubMed2002

The comparison of clinical and hormonal parameters in PCOS patients treated with metformin and GnRH analogue.

In this study, our aim was to compare the effects of metformin and gonadotropin releasing hormone (GnRH) analogues in clinical and hormonal parameters in women with polycystic ovary syndrome (PCOS). There were 50 women with PCOS who were included in our study and they were divided into two groups. In this randomized trial, metformin (850 mg, two times per day) was administered to the first group and GnRH analogue (goserelin 3.6 mg, every 28 days) was given to the second group for 3 months. Because of the previous treatments, PCOS patients served as their own controls. The results of 42 women who completed the study were evaluated. Insulin resistance was not ascertained in patients. Metformin treatment resulted in a significant decline in mean body mass index, body weight, circumferences of waist and hip and total hirsutismus score. There was a significant decrease in luteinizing hormone (LH) levels and a significant increase in follicle stimulating hormone (FSH), progesterone, and sex hormone binding globulin (SHBG) concentrations. No changes in fasting glucose and insulin levels were observed. The GnRH analogue resulted in a significant increase in FSH and SHBG levels and a significant decrease in LH, total testosterone, dehydroepiandrosterone sulfate (DHEAS) levels and LH to FSH ratio and an improvement in hirsutism scores. Metformin and GnRH analogues had effects upon the abnormal steroid-gonadotropin metabolism and the clinical findings of hyperandrogenism with different mechanisms.

Adult↗

PubMed2003

Inhibin B levels on cycle day 3 to predict the ovulatory response in women with PCOS undergoing ovulation induction via low dose step-up gonadotropin protocol.

BACKGROUND: In this prospective clinical single blind study, we aimed to investigate whether day 3 serum inhibin B levels in women with polycystic ovarian syndrome(PCOS) are of predictive value for the estimation of the ovarian response to gonadotropins. METHODS: Ovulation induction with low dose step-up gonadotropin protocol, starting with 75 IU/day, was performed for 30 cycles on 25 patients with PCOS. Day 3 serum inhibin B, follicle-stimulating hormone(FSH) and estradiol, and midluteal serum progesterone levels were measured during each cycle. The correlations between day 3 inhibin B levels and day 3 FSH, day 3 estradiol and midluteal progesterone measurements, as well as the amount of gonadotropin required to provide an ovulatory cycle were investigated. RESULTS: Five (27.8%) out of 18 cycles with day 3 inhibin levels <50.0 pg/ml; and 11 (91.7%) out of 12 cycles with levels > or = 50.0 pg/ml were ovulatory (chi(2)=9.38, p<0.01). Moreover, day 3 inhibin B levels had statistically significant negative correlation with the gonadotropin used; and significant positive correlation with the midluteal progesterone levels (p<0.05). There wasn't any significant relation between day 3 FSH and estradiol levels with the gonadotropin used and progesterone levels. CONCLUSIONS: It has been observed that as day 3 serum inhibin B levels increased in women with PCOS, the ovulatory response to gonadotropins and the rate of ovulatory cycles increased significantly.

Adult↗

PubMed2004

Treatment of PCOS with metformin and other insulin-sensitizing agents.

A significant proportion of women with polycystic ovary syndrome (PCOS) suffer from insulin resistance and compensatory hyperinsulinemia. Growing evidence indicates that elevated serum insulin induces hyperandrogenism, which in turn leads to anovulation and infertility. Hyperinsulinemia also contributes to the increased risk for cardiovascular disorders and type 2 diabetes mellitus. These concepts provide a rationale for therapies focused on treatments of insulin resistance. Metformin is the most extensively studied insulin-sensitizing agent for the treatment of women with PCOS. Use of metformin leads to a decrease in serum insulin and androgen levels, as well as an improvement in ovulatory function. Other insulin-sensitizing agents studied in women with PCOS include troglitazone, rosiglitazone, pioglitazone, and D-chiro-inositol.

Female↗

PubMed2006

Risk of T2DM and impaired fasting glucose among PCOS subjects: results of an 8-year follow-up.

Women with polycystic ovary syndrome (PCOS) often develop type 2 diabetes mellitus (T2DM). To determine the magnitude of risk of developing T2DM among women with PCOS, development of T2DM was prospectively assessed among women who had T2DM (n = 97) and controls (n = 95) using Kaplan-Meier survival analysis and Cox proportional hazards modeling. The women with T2DM had higher baseline weight (body mass index, P < 0.01) and lower insulin sensitivity (homeostasis assessment model of insulin resistance, P < 0.01). The 8-year incidence rate among cases and controls was 13.4% and 5.8%, respectively (relative risk = 2.3). Obese cases had a fivefold risk of T2DM developing (P < 0.01) compared with age-adjusted obese controls, indicating significant interaction between PCOS and obesity to effect T2DM risk.

Adult↗